During the present reporting period, our research in this area was limited due to severe reductions in available research resources. Nevertheless, we carried out research in three distinct domains - first, continued research into the basic brain mechanisms of action of the anti-nicotine smoking-cessation medication varenicline, second, research into the existence of cannabinoid CB2 receptors in the brain, and third, setting up a reward delay discounting behavioral model in our labortory. Our verenicline work during the present reporting period was a follow-up to our extensive previous research on varenicline in which we proved that varenicline's alpha4beta2 nicotinic partial agonist properties are essential to its therapeutic effect on smoking cessation while its alpha7 nicotinic agonist properties are irrelevant to its therapeutic action. Thus, future anti-nicotine-addiction anti-smoking pharmacotherapies can be designed with only alpha4beta2 nicotinic partial agonist properties - thus enhancing therapeutic efficacy and diminishing the liklihood of producing unwanted side effects. In the cannabinoid and endocannabinoid realm of research, the existence of cannabinoid CB2 receptors in the brain has been heretofore controversial. Most evidence has heretofore suggested that only CB1 cannabinoid receptors are found in brain and central nervous system while cannabinoid CB2 receptors are restricted to the body's periphery - primarily in the immune system. However, this view has been challenged by recent claims that CB2 receptors are present in the central nervous system and by recent claims that CB2 receptors modulate synaptic activity. Therefore, we used highly selective CB2 agonists and antagonists, combined with the use of CB1 and CB2 receptor gene-deleted mice, to study CB2 involvement in cocaine's behavioral and neurochemical effects. We found that the CB2 receptor-selective agonist JWH133 attenuates intravenous cocaine self-administration in wild-type and CB1 gene-deleted mice, but not in CB2 gene-deleted mice. This effect was abolished by the CB2 receptor-selective antagonist AM630. To confirm our findings, we also used the CB2-selective agonist GW405833 and found a similar inhibition of intravenous cocaine self-administration in wild-type mice. Under progressive-ratio reinforcement conditions, we found that JWH133 inhibits incentive motivation to self-administer cocaine, as evidenced by strong reductions in the progressive-ratio break-point. Similar effects were found when JWH133 was administered intra-nasally (for direct passage into the brain via the cribiform plate) or administered by direct intracerebral microinjections of JWH133 into the nucleus accumbens. Again, the effect was seen in wild-type but not in CB2 receptor gene-deleted mice. JWH133 by itself was found to have no reinforcing or aversive effects, as assessed by intravenous self-administration and by conditioned place preference/aversion experiments. Further, JWH133 inhibited cocaine-enhanced locomotion in wild-type and CB1 gene-deleted mice, but not in CB2 gene-deleted mice. JWH133 by itself had an inhibitory effect on locmotion, both with systemic administration and with intracerebral microinjection into the nucleus accumbens in wild-type and CB1 gene-deleted mice, but not in CB2 gene-deleted mice. The CB2 selective antagonist AM630 had a stimulatory effect on locomotion, both with systemic administration and with intracerebral microinjection into the nucleus accumbens in wild-type and CB1 gene-deleted mice, but not in CB2 gene-deleted mice. JWH133 by itself inhibited extracellular nucleus accumbens dopamine as measured by real-time in vivo brain microdialysis. JWH133 also inbited basal and cocaine-enhanced extracellular nucleus accumbens dopamine as measured by real-time in vivo brain microdialysis. This effect was blocked by the CB2-selective antagonist AM630. By itself, AM630 - microinjected intracerebrally into the nucleus accumbens - aumented basal extracellular nucleus accumbens dopamine. We conclude that CB2 cannabinoid receptors exist in the brain, that CB2 receptors functionally modulate the meso-accumbens dopamine system, that CB2 receptors functionally modulate dopamine-mediated behaviors, and that the brain CB1 and Cb2 receptor-linked neural systems may functionally antagonize each other in a reciprocal mutually antatagonistic manner. Such mechanistic knowledge can aid in the search for new and effective pharmacotherapeutic compounds for the treatment of drug addiction and dependence. In additiom, during this reporting period, we introduced a new animal model into our battery of preclinical animal models of addiction. At the human level, inability to delay gratification is a pathognomonic symptom of drug addiction. Therefore, we have introduced a reward delay discounting task into our laboratory. In this task, laboratory rats are presented with two wall-mounted levers in their test chambers. Depression of one lever delivers a food reward immediately. Depression of the other lever delivers a larger reward after a delay period ranging up to 60 seconds. The animal must choose whether it desires a small immediate reward or a larger delayed reward. In this manner, impulsive choice can be measured and quantified. It is our intention to use this new animal model to measure the effect of chronic administration of addictive drugs on impulsive choice, and also to determine whether any of our putative anti-addiction pharmacotherapies can change addictive-drug-altered impulsice choice in a putatively therapeutic direction. We believe that the addition of this new model - derived from behavioral economics - gives us an entirely new clinically-relevant perspective to evaluate potentially therapeutic anti-addiction anti-craving anti-relapse medications at the preclinical animal model level.